tbuckley/cabot-search huggingface dataset:
P1129: ACALABRUTINIB IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) MARGINAL ZONE LYMPHOMA (MZL): RESULTS OF A PHASE 2, MULTICENTER, OPEN-LABEL TRIAL
Authors: P. Strati, M. Coleman, D. Stevens, S. Ma, C. Patti, M. Levy, I. S. Lossos, P. Ramakrishnan Geethakumari, S. Lam, R. Calvo, K. Higgins, L. Budde
Journal: HemaSphere (2022)

Background: MZL is a rare indolent B-cell malignancy considered incurable at recurrent stage. Bruton tyrosine kinase (BTK) inhibitors have produced durable responses in patients (pts) with R/R MZL. Acalabrutinib (acala) is a potent next-generation BTK inhibitor with high selectivity for BTK. Aims: We report data for acala monotherapy from the R/R MZL cohort (phase 2) of a phase 1b/2 clinical trial (NCT02180711). Methods: Pts with histologically confirmed MZL, ECOG performance status ≤2, and ≥1 prior therapy (including ≥1 CD20-directed regimen) received oral acala 100 mg twice daily until disease progression or unacceptable toxicity ± R. The primary objective was overall response rate (ORR; Lugano criteria as assessed by the investigator). Secondary objectives were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively (no formal hypothesis testing). Results: Forty-two pts received acala (median age 69 y [range 42–84]; median 2 prior systemic regimens [range 1–4]). MZL subtypes were extranodal (43%), nodal (31%), and splenic (26%). At data cutoff (Oct 15, 2021), median follow-up duration was 10.7 mo (range 0.4–42.8). Sixteen (38%) pts discontinued acala, most commonly due to disease progression (26%). Among pts evaluable for response (n=37; 3 pts had not reached the first assessment timepoint and 2 pts exited the study without response assessment), ORR was 54% (95% CI 37%–71%) with 6 complete (16%) and 14 partial (38%) responses; 17 (46%) pts had stable disease. ORRs in extranodal, nodal, and splenic subtypes were 65%, 44%, and 45%, respectively. Median time to initial response was 3.0 mo; median DOR was 19.3 mo (95% CI 8.4–not estimable). Median PFS was 27.4 mo with a 12-mo PFS rate of 66%. Four pts died (disease progression, n=2; transformation to diffuse large B-cell lymphoma after stopping treatment, n=1; adverse event [AE], n=1 [septic shock unrelated to treatment]); median OS was not reached. Treatment was well tolerated with most AEs being grade 1 or 2. Sixteen pts (38%) had grade ≥3 AEs, most commonly (in ≥2 pts) anemia, dyspnea, neutrophil count decrease (n=3 each), fatigue, thrombocytopenia, and neutropenia (n=2 each). AEs led to treatment discontinuation in 2 pts (grade 3 hypotension and grade 1 myalgia). Among AEs of clinical interest, hypertension was reported in 2 pts (both grade 2); no cases of atrial fibrillation/flutter or major hemorrhage were reported. Summary/Conclusion: These early results indicate that acala is efficacious and well tolerated in pts with R/R MZL. The AE profile is consistent with the known safety profile of acala.
Numeric Error in Table 1
Authors: Anne Goei, Harvard Chan
Journal: JAMA Surgery (2022)

Thomas S. Huber, MD, PhD; Scott A. Berceli, MD, PhD; Salvatore T. Scali, MD; Dan Neal, MS; Erik M. Anderson, MD; Michael Allon, MD; Alfred K. Cheung, MD; Laura M. Dember, MD; Jonathan Himmelfarb, MD; Prabir Roy-Chaudhury, MD, PhD; Miguel A. Vazquez, MD; Charles E. Alpers, MD; Michelle L. Robbin, MD; Peter B. Imrey, PhD; Gerald J. Beck, PhD; Alik M. Farber, MD, MBA; James S. Kaufman, MD; Larry W. Kraiss, MD; Wanpen Vongpatanasin, MD; John W. Kusek, PhD; Harold I. Feldman, MD, MSCE
Risk factors for multisystem inflammatory syndrome in children – A population-based cohort study of over 2 million children
Authors: Samuel Rhedin, Cecilia Lundholm, AnnaCarin Horne, Awad I. Smew, Emma Caffrey Osvald, Araz Haddadi, Tobias Alfvén, Robin Kahn, Petra Król, Bronwyn Haasdyk Brew, Catarina Almqvist
Journal: The Lancet Regional Health - Europe (2022)

Although severe acute COVID-19 is rare in children, SARS-CoV-2 infection can trigger the novel post-infectious condition multisystem inflammatory syndrome in children (MIS-C). Increased knowledge on risk factors for MIS-C could improve our understanding of the pathogenesis of the condition and better guide targeted public health interventions. The aim of the study was to assess risk factors for MIS-C with the aim to identify vulnerable children.A register-based cohort study including all children and adolescents <19 years born in Sweden between March 1, 2001- December 31, 2020 was performed. Data on sociodemographic risk factors and comorbidities (sex, age, parental region of birth, parental education, asthma, autoimmune disease, chromosomal anomalies, chronic heart disease, chronic lung disease, obesity, life-limiting condition) were retrieved from national health and population registers. The outcome was MIS-C diagnosis according to the Swedish Pediatric Rheumatology Quality Register during March 1, 2020 - December 8, 2021.Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression analysis. Incidence rates per 100 000 person-years were calculated assuming a Poisson distribution.Among 2 117 443 children included in the study, 253 children developed MIS-C, corresponding to an incidence rate of 6·8 (95% CI: 6·0-7·6) per 100 000 person-years. Male sex (HR 1·65, 95% CI: 1·28-2·14), age 5-11 years (adjusted HR 1·44, 95% CI: 1·06-1·95 using children 0-4 years as reference), foreign-born parents (HR 2·53, 95% CI: 1·93-3·34), asthma (aHR 1·49, 95% CI: 1·00-2·20), obesity (aHR 2·15, 95% CI: 1·09-4·25) and life-limiting conditions (aHR 3·10, 95% CI: 1·80-5·33) were associated with MIS-C. Children 16-18 years had a reduced risk for MIS-C (aHR 0·45, 95% CI: 0·24-0·85).We report increased risks for MIS-C in children with male sex, age 5-11 years, foreign-born parents, asthma, obesity, and life-limiting condition. Knowing these risk populations might facilitate identification of children with MIS-C and potentially guide targeted public health interventions. Nevertheless, the absolute risks for MIS-C were very low.Financial support was provided from the Swedish Research Council (grant no 2018-02640), the Swedish Heart-Lung Foundation (grant no 20210416), the Asthma and Allergy Association, Ake Wiberg foundation, the Samariten Foundation, the Society of Child Care, and Region Stockholm.
P711: KINETICS OF CITED2 GENE EXPRESSION IN CHRONIC MYELOID LEUKEMIA PATIENTS
Authors: B. Atef, S. El-Ashwah, L. M. Saleh, H. Gawish, M. Nasr
Journal: HemaSphere (2022)

Background: In chronic myeloid leukemia (CML), BCR-ABL1 oncoprotein induces overexpression of STAT5 and its target genes. Some of these genes are involved in regulating the leukemic stem cells (LSCs) cell cycle. CITED2 gene controls the balance between the proliferation and the quiescence states of the LSCs that resist tyrosine kinase inhibitors (TKIs). Recently, studies reported that adding peroxisome proliferator‐activated receptor γ agonists (approved for type 2 Diabetes mellitus treatment) to TKI therapy may decrease the transcription of STAT5 and its target genes, eliminate the quiescent LSCs and ameliorate the patients’ response. Aims: The aim of the study is to clarify the value of combining the glitazones with the TKIs in the treatment of denovo CML CP patients as regard the patients’ response and effect of this combination therapy on the expression of CITED2 gene. Methods: In a context of a clinical trial (approved by the ethical Committee of the Faculty of Medicine Mansoura University), eligible denovo patients of CML chronic phase (N=26) were treated with imatinib 400 mg combined and pioglitazone 15 mg (off label use) daily for 6 months after having their consent. Responders continued on same TKI and their sequential BCR/ABL Q-PCR was monitored. The non-responder patients were switched to another line and excluded. Pre and post-treatment samples were collected to assess the expression levels of CITED2 gene. Results: The study group included 15 males (57.7%) and 11 females (42.3%) with a mean age of 43.2 years. Their median BCR-ABL gene expression before treatment was 79% (range = 0.63-380) that decreased to 3.65% (range = 0.05-20) and 0.750 % (range = 0.002-46) on 3rd and 6th months post-treatment. Among the study group 100% of the patients achieved hematological response (HR) at 3 months. At 6 months 65.4% of the patients had response more than CCyR and 23% of them had MMR at 6 months respectively. The most frequent complains among patients were increase body weight and edema (p value < 0.001). The median of CITED2 gene pre-treatment and post-treatment expression levels were: 276.3 (range= 1-241221.7) and 2.6 (range= 0.006-86475.3) with a significant decrease in expression (p=0.005) after the combined treatment. Summary/Conclusion: Pioglitazone in combination with imatinib improved the patients’ response and downregulate the expression of the CITED2 overexpressed gene. Longer follow up is planned and needed to confirm whether it can effectively induce more deep molecular response among the patients or not.
P420: FORCING LEUKAEMIC STEM CELL TO LEAVE QUIESCENT STATE BY INHIBITING HEDGEHOG, NOTCH AND WNT/BETA-CATENIN SIGNALLING PATHWAYS
Authors: D. Láinez-González, J. Serrano-López, P. Llamas-Sillero, J. M. Alonso-Dominguez
Journal: HemaSphere (2022)

Background: Acute myeloid leukaemia (AML) is a clonal neoplasm with a high relapse rate. It is thought that this relapse is caused by chemoresistance of leukaemic stem cells (LSC) due to their quiescent state. Numerous signalling pathways have been described that regulate quiescence. Key players in this setting are the Hedgehog (Hh), Notch and WNT/β-Catenin pathways. Current chemotherapeutic agents target the cell population in the proliferative phase of the cell cycle. Therefore, cells in quiescence are not affected by drugs such as cytarabine (AraC). Theoretically, forcing quiescent cells into the proliferative phase would help to eradicate the LSC population and avoid relapses. Aims: To force quiescent LSC to enter cell cycle by inhibiting Hedgehog, Notch or/and Wnt/Beta-Catenin. Methods: Three acute myeloid leukemia cell lines, HL60, OCI-AML3 and KASUMI1, and 13 primary samples were used to study cell cycle and cytotoxicity. They were treated during 24-48 hours with Glasdegib, Nirogacestat and PRI-724 which target Smoothened (Hedgehog), Gamma-Secretase (Notch) and Beta-Catenin (Wnt) proteins respectively. Studies of drug combination were also performed to inhibit different signaling pathways at the same time. Cytarabine was employed during 48-72 hours in cell lines or during 24-48 hours in primary samples. Cytotoxicity was analyzed by WST8 assay in cell lines and flow cytometry in primary samples by using KI67 and Annexin V. Cell cycle was study by flow cytometry using KI67 and 7AAD, and in primary samples CD45, CD34 and CD38 antibodies were used to detect LSC. Cell lines experiments were triplicated. Results: In HL60, double inhibition during 48h of Hedgehog and Notch with 15 nM Glasdegib + 5 nM Nirogacestat reduced quiescent state in 67.27% compared with DMSO. Furthermore, this proposed treatment in combination with 109.1 nM AraC decreased 27-70% viability compared with AraC monotherapy at 72h. Similar results were obtained in OCI-AML3, in which the proposed treatments reduced quiescent phase compared with control, but no changes were observed in viability. On the other hand, in KASUMI1 there were no differences either in cell cycle or viability assay. In primary CD34+ samples, when Hedgehog and Notch were inhibited during 48h, quiescent state decreased in 33.06%, but no effects in viability were observed. Image:Summary/Conclusion: The number of primary samples should be increased to shed light on the efficacy of this interesting therapeutic strategy. Nevertheless, inhibition of Hh, Notch and WNT pathways reduce the quiescent population either measuring the disease as a whole or looking at the LSC population. Differences observed between different AML cell lines regarding increase of the citotoxicity might be explained by AML genetic heterogeneity.
P1290: A TISSUE-BASED EX VIVO CULTURE SYSTEM TO ANTICIPATE TEHRAPY RESPONSE IN LYMPHOMA.
Authors: A. Santamaria-Martínez, J. Epiney, D. Srivastava, D. Tavernari, D. Milowich, I. Letovanec, G. Ciriello, A. Cairoli, E. Oricchio
Journal: HemaSphere (2022)

Background: B-cell malignancies are a heterogenous group of malignancies that acquire multiple genomic alterations over time and in which the interactions between tumor cells and the tumor microenvironment (TME) are often important for tumor growth. Modeling lymphoma ex vivo has been hampered by the lack of suitable 3D models and the complexity of translating organoid technology from other cancer types into lymphoma. Hence, research mainly relies on the use of transgenic and xenograft animal models. Aims: We wanted to develop a method to maintain lymphoma tissue explants in culture which could be used to study lymphoma pathogenesis and to test response to anti-cancer therapies directly on patient tumor tissues. We call these tumor tissue fragments lymphomoids. Methods: We have designed an ex vivo culture system to maintain lymphoma tissues in culture for several weeks. We have tested this technology on murine models of lymphoma and on tissue biopsies obtained from 9 different patients diagnosed with different lymphoma subtypes. To confirm that our method supports tissue architecture for several weeks we have performed multiparametric FACS analyses, single-cell RNA sequencing, high-plex spatial proteomics profiling, and spatial transcriptomics analyses. Results: With our approach, we are able to preserve the tissue composition and the interactions between tumor cells and their microenvironment ex vivo for three to four weeks. The transcriptional profile of tumor tissue biopsies was highly conserved in lymphomoids, indicating that we are able to maintain the tissue heterogeneity present in the original tumors. To anticipate sensitivity to anti-cancer therapies, we have tested and compared response to targeted therapies and immunotherapy on lymphomoids obtained from the 9 human primary lymphomas. Histopathological and spatial transcriptomic analyses showed patient-specific sensitivity to particular compounds and revealed features on the tumor tissue composition associated with resistance or response to therapies. Summary/Conclusion: Overall, we have developed a system to maintain patient-derived lymphomoids in culture which allows to anticipate sensitivity and resistance to anti-cancer therapies, and it could potentially be used to identify the best therapeutic options for each patient in a clinical setting.
P666: ACALABRUTINIB ± OBINUTUZUMAB VS OBINUTUZUMAB + CHLORAMBUCIL IN TREATMENT-NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA: 5-YEAR FOLLOW-UP OF ELEVATE-TN
Authors: J. P. Sharman, M. Egyed, W. Jurczak, A. Skarbnik, K. Patel, I. W. Flinn, M. Kamdar, T. Munir, R. Walewska, L. M. Fogliatto, Y. Herishanu, V. Banerji, G. Follows, P. Walker, K. Karlsson, P. Ghia, A. Janssens, F. Cymbalista, E. Ferrant, W. G. Wierda, V. Munugalavadla, T. Yu, M. H. Wang, J. A. Woyach
Journal: HemaSphere (2022)

Background: For ELEVATE-TN (NCT02475681), we previously reported superior efficacy of acalabrutinib (A) ± obinutuzumab (O) vs O + chlorambucil (Clb) in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) at 28.3 and 46.9 months median follow-up. Aims: To report the updated efficacy and safety results from the ELEVATE-TN study after a median follow-up of 5 years. Methods: Patients were randomized to A+O, A, or O+Clb after informed consent was obtained. Patients who progressed on O+Clb could cross over to A monotherapy. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: A total of 535 patients (A+O, n=179; A, n=179; O+Clb, n=177) had a median age of 70 years; 63% had unmutated IGHV and 9% had del(17p). At a median follow-up of 58.2 months (range, 0.0–72.0; data cutoff Oct 1, 2021), median PFS was not reached (NR) (hazard ratio [HR]: 0.11) for A+O and A (HR: 0.21) vs 27.8 months for O+Clb (both P<0.0001). The estimated 60-month PFS rates were 84% (A+O), 72% (A), and 21% (O+Clb). In patients with unmutated IGHV, the median PFS was NR for A+O and A vs 22.2 months among patients in the O+Clb arm (HR: 0.06 [A+O] and 0.12 [A]; both P<0.0001); estimated 60-month PFS rates were 82% (A+O), 72% (A), and 6% (O+Clb). In patients with del(17p), the median PFS was NR and 64.1 months for A+O and A vs 17.7 months for O+Clb (HR: 0.21, P=0.0031 [A+O]; HR: 0.29, P=0.0130 [A]); estimated 60-month PFS rates were 75% (A+O), 71% (A), and 27% (O+Clb). Median OS was NR in any treatment arm, and significantly longer in the A+O vs O+Clb arms (HR: 0.55; P=0.0474); estimated 60-month OS rates were 90% (A+O), 84% (A), and 82% (O+Clb). ORR was significantly higher with A+O (96%; 95% CI 92–98) and A (90%; 85–94) vs O+Clb (83%; 77–88; P<0.0001 [A+O], P=0.0499 [A]). Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were higher with A+O (29%/3%) vs O+Clb (13%/1%); 13%/1% had CR/CRi with A; CR increased since the interim analysis (previously 21% [A+O] and 7% [A]). Adverse events (AEs) and treatment exposure are shown in the Table. Treatment is ongoing in 65% (A+O) and 60% (A) of patients; the most common reasons for treatment discontinuation were AEs (17% [A+O], 16% [A], 14% [O+Clb]) and progressive disease (6%, 10%, 2%, respectively). Crossover from O+Clb to A occurred in 72 (41%) patients; 25% of these patients discontinued A (10% due to AEs and 11% due to progressive disease). Image:Summary/Conclusion: After 5 years of follow-up, efficacy and safety of A+O and A monotherapy were maintained, with significantly longer OS in the A+O arm compared with O+Clb.
P710: CLINICAL STUDY ON THE RELATIONSHIP BETWEEN NON-ABL1 KINASE REGION MUTATION AND TKI DRUG RESISTANCE AND DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA
Authors: W. xianwei, L. xiaodong
Journal: HemaSphere (2022)

Background: The emergence of small molecule tyrosine kinase inhibitors (The Tyrosine Kinase Inhibitors, TKI) has gradually transformed chronic myelocytic leukemia (CML) from a fatal malignant disease into a chronic disease, while ABL1 kinase Kinase Domain (KD) mutation is the main reason for poor efficacy or resistance to TKIs. In recent years, with the clinical application of Next Generation Sequencing (NGS) technology, it has been found that CML patients are often accompanied by non-ABL1 kinase region gene mutations, but whether these accompanying mutations are related to the efficacy of TKIs and disease progression in CML? still uncertain. This study retrospectively analyzed the correlation between CML with non-ABL1 KD mutation and TKI efficacy and disease progression, in order to provide basis and scientific guidance for further accurate diagnosis and treatment of CML patients. Aims: To investigate the relationship between CML associated with non ABL1 Kinase Domain (KD) mutation and TKI efficacy and disease progression. Methods: 108 blood tumor related genes in 120 patients with CML were detected by Next-generation sequencing (NGS). The non ABL1 KD mutations and their relationship with relevant clinical information and ABL1 KD mutation were analyzed. Results: Non ABL1KD mutations were detected in 58 patients (48%), and the mutation proportion of patients with additional chromosome abnormalities (63%) was significantly higher than that of patients without additional chromosome abnormalities (34%) (P=0.003). In the analysis of mutation proportion in patients with different stages of CML, the mutation proportion in blastic phase(73%), accelerated phase (67%) and chronic phase (42%) decreased gradually (P=0.031). The proportion of WT1 mutation and transcriptional regulation related mutations in patients with AP CML (WT1+: 17%, P=0.027; Transcriptional regulatory mutations 42%, P=0.001) were higher than those in CP. In the analysis of TKI treatment response, the proportion of mutations detected in the best response group (30%), warning group (52%) and drug resistance group (61%) increased gradually (P=0.018). The proportion of RUNX1 mutation in TKI treatment failure group (17%) was higher than that in warning group (2%) (P=0.029). The proportion of ABL1 KD mutation in CML patients with non ABL1 KD mutation (60%) was significantly higher than that in patients without non ABL1 KD mutation (36%) (P=0.022). Summary/Conclusion: Non ABL1 KD mutations are closely related to TKI efficacy and disease progression, while WT1 and RUNX1 mutations may be new molecular targets for accurate diagnosis of CML.
Amphicrine Medullary Thyroid Carcinoma — a Case-Based Review Expanding on Its MUC Expression Profile
Authors: Hena Khandakar, Shipra Agarwal, Mehar Chand Sharma, Devasenathipathy Kandasamy, Chandrasekhar Bal, Yashvant Rathode, Rijuta Aphale
Journal: Endocrine Pathology (2022)
P414: RNA MODIFICATION-FOCUSED CRISPR-CAS9 SCREEN REVEALS POTENTIAL THERAPEUTIC TARGETS MEDIATING CHEMORESISTANCE IN AML
Authors: M. Kienhöfer, C. Pauli, S. Delaunay, C. Rohde, M. F. Blank, D. Heid, M. Frye, C. Müller-Tidow
Journal: HemaSphere (2022)

Background: Acquired therapy resistance is one of the main causes of death in Acute Myeloid Leukemia (AML). RNA-modifying proteins (RMP) are a diverse group of enzymes responsible for the deposition and the removal of over 170 chemical modifications, impacting key features of RNA biology. The RMPs represent a new focus for target therapies. Aims: The objective of the current study is to uncover how RNA-modifying proteins affects resistance to treatment in AML. Methods: A CRISPR-Cas9-based screening approach was utilized to study RNA-modifying proteins in an AML cell line and a derived cell line resistant to cytarabine. The library pool targeted 150 RNA modifying enzymes, the 250 most abundant expressed snoRNAs in AML, as well as a group of control genes and non-targeting sgRNAs. A lentiviral system was used to introduce the CRISPR system. Multiplicity of infection (MOI) was held under 0.3 to guarantee one gene knockout per cell. Post-infection, the cell lines were divided into a control and a treatment group. The treatment group was stimulated with increasing doses of cytarabine over 22 days. Samples were analyzed via NGS. Results: In the CRISPR screen, we observed that many of the gene knockouts led to cell depletion. Overall, 37 genes knockouts were depleted in the control group of both cell lines without additional drug treatment, suggesting that the related genes are required for survival and/ or proliferation. Further, 28 RNA-modifying enzymes and 15 snoRNAs were altered upon drug treatment in at least the parental or the resistant cell line. Interestingly, 15 of those 28 enzymes show additional effects on proliferation. Based on this data, we chose a methyltransferase responsible for specific modification on tRNAs for further analysis. Single knockout of the enzyme sensitized different AML cell lines for cytarabine treatment and showed impairment of proliferation as well as the ability to form colonies. Summary/Conclusion: RNA modifications promote several hallmarks of cancer. This study reports the involvement of specific RNA-modifying enzymes for therapy resistance and proliferation in AML. However, it remains unclear whether these enzymes are dysregulated in leukemic cells and therefore could display a targetable vulnerability. In addition, further studies of the affected cellular pathway could contribute to a better understanding of the underlying resistance mechanisms.